Synthesis of 7-membered carbocyclic compound having diexomethylene groups

ABSTRACT

The present invention relates to a synthesis of a 7-membered carbocyclic compound having diexomethylene groups, more particularly to a synthesis of a 7-membered carbocyclic compound having diexomethylene groups, a novel compound having the structure represented by the following Chemical Formula 1, from trimethylsilanylmethyl-allenol derivative by the intramolecular Prins cyclization using Lewis acid. The 7-membered carbocyclic compound is a useful intermediate for synthesis of other multicyclic compounds.  
                 
 
     In Chemical Formula 1, R 1  is a C 1  to C 6  alkyl group, and R 2  and R 3  is respectively a hydrogen atom, or R 1 , R 2  and R 3  may be connected with neighboring substituents to form a 5 to 10-membered aliphatic or aromatic ring.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a synthesis of a 7-memberedcarbocarbocyclic compound having diexomethylene groups, moreparticularly to a synthesis of a 7-membered carbocyclic compound havingdiexomethylene groups, a novel compound having the structure representedby the following Chemical Formula 1, from trimethylsilanylmethyl-allenolderivative by the intramolecular Prins cyclization using Lewis acid. The7-membered cyclic compound is a useful intermediate for synthesis ofother multicyclic compounds.

In Chemical Formula 1, R¹ is a C₁ to C₆ alkyl group, and R² and R³ isrespectively a hydrogen atom, or R¹, R² and R³ may be connected withneighboring substituents to form a 5 to 10-membered aliphatic oraromatic ring.

2. Description of the Related Art

7-membered carbocyclic compounds are important ingredients ofbiologically active natural substances and medicines. Recently, they aregaining interest in genetics because they are known to take part in celldivision. For example, colchicine, which is known to be effective intreating gout [J. Org. Chem. 1985, 50, 3425-3427], is a tricycliccompound having a 7-membered ring. According to a recent report,colchicine derivatives have high cell toxicity against general cancercells and their resistant MDRs.

Since 7-membered carbocyclic compounds have good biological activity,development of a 7-membered carbocyclic compound with a new structure isa prerequisite for drug researches.

A cyclic compound having diexomethylene groups can be expanded to othermulticyclic compounds through Diels-Alder reactions. Therefore, thecompound represented by Chemical Formula 1, which has diexomethylenegroups, is a very useful intermediate in synthesizing a multicycliccompound via Diels-Alder reactions.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a 7-memberedcarbocyclic compound having diexomethylene groups, which is representedby Chemical Formula.

It is another object of the present invention to provide a method forsynthesizing the novel compound represented by Chemical Formula 1 from atrimethylsilanylmethyl-allenol derivative by the intramolecular Prinscyclization using Lewis acid.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is characterized by a 7-membered carbocycliccompound having a new structure, which is represented by the followingChemical Formula 1:

In Chemical Formula 1, R¹ is a C₁ to C₆ alkyl group, and R² and R³ isrespectively a hydrogen atom, or R¹, R² and R³ may be connected withneighboring substituents to form a 5 to 10-membered aliphatic oraromatic ring.

Also, the present invention is characterized by a method of synthesizingthe compound represented by Chemical Formula 1 from atrimethylsilanylmethyl-allenol derivative by the intramolecular Prinscyclization in the presence of Lewis acid.

Hereinafter, the present invention is described in more detail.

The 7-membered carbocyclic compound represented by Chemical Formula 1,which is provided by the present invention, is a novel compound havingdiexomethylene groups, and it can be used as an active ingredient ofmedicines, or intermediate of synthesizing multicyclic compounds in thefield of medicine and precise chemistry.

Specific examples of the compound provided by the present inventioninclude:

-   -   a compound wherein R¹ is a C₁ to C₃ alkyl group, and R² and R³        is respectively a hydrogen atom;    -   a compound wherein R¹ and R² are connected with each other to        form a 5 to 10-membered aliphatic or aromatic ring, and R³ is a        hydrogen atom; and    -   a compound wherein R² and R³ are connected with each other to        form a 5 to 10-membered aliphatic or aromatic ring, and R¹ is a        hydrogen atom.

The present invention also provides a method of synthesizing thecompound represented by Chemical Formula 1 from atrimethylsilanylmethyl-allenol derivative by the intramolecular Prinscyclization in the presence of Lewis acid.

For the Lewis acid, such common Lewis acids as trimethylsilyltrifluoromethanesulfonate (TMSOTf) or indium halide (InX₃, X═Cl or Br)can be used. Most preferably, TMSOTf is used. Preferably, the Lewis acidis used in 1.0 to 1.5 equivalent of the starting material, atrimethylsilanylmethyl-allenol derivative. For the reaction solvent,common organic solvents such as diethyl ether, tetrahydrofuran,dichloromethane, chloroform and ethyl acetate can be used. Mostpreferably, diethyl ether is used. The reaction is performed at from−90° C. to room temperature (25° C.) for about 3 to 5 hours.

Since the aforementioned intramolecular Prins cyclization isindustrially very probable because it is relatively simple and offersgood yield.

The compound represented by Chemical Formula 1 is useful in the field ofmedicine and precise chemistry. Because the compound represented byChemical Formula 1 has diexomethylene groups, other multicycliccompounds can be prepared from it by Diels-Alder reactions.

Hereinafter, the present invention is described in more detail throughExamples. However, the following Examples should not be construed aslimiting the scope of the present invention.

EXAMPLES Example 1 Synthesis of1-methyl-2,3-dimethylene-8-oxa-bicyclo[3.2.1]octane

1.50 mL of diethyl ether was added to5-hydroxy-7-trimethylsilanylmethyl-nona-7,8-diene-2-one (86 mg, 0.36mmol) under nitrogen atmosphere. While stirring at −78° C.,trimethylsilyl trifluoromethanesulfonate (TMSOTf; 64.7 μL, 0.36 mmol)was added. While stirring the reaction mixture, the reaction temperaturewas slowly increased to room temperature for 3 hours. The reactionmixture was stirred at room temperature for 30 minutes. After thereaction was completed, H₂O was added. After stirring for about 5minutes, the reaction mixture was diluted with ethyl acetate (EtOAc) andwashed with water and saturated brine. The organic layer was separatedfrom the reaction mixture and dried with anhydrous magnesium sulfate(MgSO₄). The solvent was removed under reduced pressure and theremaining material was purified with column chromatography(EtOAc/n-hexane=1/5) to obtain 51 mg of the product (94%).

¹H NMR (300 MHz, CDCl₃) δ 5.17 (s, 1H), 5.29 (s, 1H), 4.78 (t, 2H, J=5.6Hz), 4.53 (s, 1H), 2.69 (d, 1H, J=12.1 Hz), 2.36 (m, 2H), 1.85 (m, 3H),1.51 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 152.51, 143.41, 112.19, 104.33,81.86, 76.23, 42.42, 37.47, 30.22, 22.87 ppm.

Example 2 Synthesis of2,3-dimethylene-1-phenyl-8-oxa-bicyclo[3.2.1]octane

1.50 mL of diethyl ether was added to4-hydroxy-1-phenyl-6-trimethylsilanylmethyl-octa-6.7-diene-1-one (110mg, 0.36 mmol) under nitrogen atmosphere. While stirring at −78° C.,TMSOTf (64.7 μL, 0.36 mmol) was added. While stirring the reactionmixture, the reaction temperature was slowly increased to roomtemperature for 3 hours. The reaction mixture was stirred at roomtemperature for 30 minutes. After the reaction was completed, H₂O wasadded. After stirring for about 5 minutes, the reaction mixture wasdiluted with EtOAc and washed with water and saturated brine. Theorganic layer was separated from the reaction mixture and dried withanhydrous MgSO₄. The solvent was removed under reduced pressure and theremaining material was purified with column chromatography(EtOAc/n-hexane=1/5) to obtain 74 mg of the product (96%).

¹H NMR (300 MHz, CDCl₃) δ 7.33 (m, 5H), 5.20 (s, 1H), 4.94 (s, 1H), 4.87(s, 1H), 4.74 (s, 1H), 3.99 (s, 1H), 2.84 (d, 1H, J=17 Hz), 2.39 (t, 1H,J=7.9 Hz), 2.29 (d, 1H, J=14.2 Hz), 2.17 (m, 2H), 1.92 (m, 1H); ¹³C NMR(75 MHz, CDCl₃) δ 153.75, 143.58, 143.10, 128.06, 127.27, 127.00,112.46, 108.18, 86.98, 76.04, 42.55, 37.17, 29.73 ppm.

Example 3 Synthesis of9,10-dimethylene-12-oxa-tricyclo[6.3.1.0^(2,7)]dodeca-2,3,5-triene

5.2 mL of diethyl ether was added to2-(1-hydroxy-3-trimethylsilanylmethyl-penta-3,4-dienyl)-benzaldehyde(358 mg, 1.30 mmol) under nitrogen atmosphere. While stirring at −78°C., TMSOTf (235 μL, 1.30 mmol) was added. While stirring the reactionmixture, the reaction temperature was slowly increased to roomtemperature for 3 hours. The reaction mixture was stirred at roomtemperature for 30 minutes. After the reaction was completed, H₂O wasadded. After stirring for about 5 minutes, the reaction mixture wasdiluted with EtOAc and washed with water and saturated brine. Theorganic layer was separated from the reaction mixture and dried withanhydrous MgSO₄. The solvent was removed under reduced pressure and theremaining material was purified with column chromatography(EtOAc/n-hexane=1/6) to obtain 185 mg of the product (77%).

¹H NMR (300 MHz, CDCl₃) δ 7.24 (m, 4H), 5.40 (s, 1H), 5.35 (d, 1H, J=4.8Hz), 5.15 (s, 1H), 5.11 (s, 1H), 4.97 (s, 1H), 4.67 (s, 1H), 3.02 (br d,1H, J=15.0 Hz), 2.37 (d, 1H, J=14.4 Hz); ¹³C NMR (75 MHz, CDCl₃) δ146.20, 143.56, 143.01, 139.90, 127.68, 120.68, 114.16, 107.22, 83.31,79.10, 38.56 ppm.

Example 4 Synthesis of9,10-dimethylene-11-oxa-tricyclo[5.3.1.0^(1,5)]undecane

1.1 mL of diethyl ether was added to2-(2-hydroxy-4-trimethylsilanylmethyl-hexa-4,5-dienyl)-cyclopentanone(70 mg, 0.26 mmol) under nitrogen atmosphere. While stirring at −78° C.,TMSOTf (48 μL, 0.26 mmol) was added. While stirring the reactionmixture, the reaction temperature was slowly increased to roomtemperature for 3 hours. The reaction mixture was stirred at roomtemperature for 30 minutes. After the reaction was completed, H₂O wasadded. After stirring for about 5 minutes, the reaction mixture wasdiluted with EtOAc and washed with water and saturated brine. Theorganic layer was separated from the reaction mixture and dried withanhydrous MgSO₄. The solvent was removed under reduced pressure and theremaining material was purified with column chromatography(EtOAc/n-hexane=1/15) to obtain 36 mg of the product (77%).

¹H NMR (300 MHz, CDCl₃) δ 5.17 (s, 1H), 5.04 (s, 1H), 4.81 (s, 2H), 4.58(t, 1H, J=6.3 Hz), 2.73 (dd, 1H, J₁=14.6 Hz, J₂=2.4 Hz), 2.35 (m, 1H),2.17 (m, 2H), 1.81 (m, 6H), 1.38 (m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ150.59, 144.25, 111.22, 103.66, 94.02, 77.70, 47.06, 41.53, 40.88,34.60, 32.77, 25.02 ppm.

Example 5 Synthesis of10,11-dimethylene-12-oxa-tricyclo[6.3.1.0^(1,6)]dodecane

1.5 mL of diethyl ether was added to2-(2-hydroxy-4-trimethylsilanylmethyl-hexa-4,5-dienyl)-cyclohexanone(100 mg, 0.36 mmol) under nitrogen atmosphere. While stirring at −78°C., TMSOTf (64.5 μL, 0.36 mmol) was added. While stirring the reactionmixture, the reaction temperature was slowly increased to roomtemperature for 3 hours. The reaction mixture was stirred at roomtemperature for 30 minutes. After the reaction was completed, H₂O wasadded. After stirring for about 5 minutes, the reaction mixture wasdiluted with EtOAc and washed with water and saturated brine. Theorganic layer was separated from the reaction mixture and dried withanhydrous MgSO₄. The solvent was removed under reduced pressure and theremaining material was purified with column chromatography(EtOAc/n-hexane=1/6) to obtain 53 mg of the product (78%).

¹H NMR (300 MHz, CDCl₃) δ 5.20 (s, 1H), 5.12 (s, 1H), 4.79 (s, 1H), 4.74(s, 1H), 4.51 (s, 1H), 2.70 (d, 1H, J=13.7 Hz), 2.15 (d, 1H, J=14.3 Hz),1.96 (m, 4H), 1.65 (m, 5H), 1.22 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ153.22, 143.83, 112.17, 106.14, 82.65, 73.73, 43.35, 42.09, 38.11,31.43, 29.61, 23.21, 20.54 ppm.

Example 6 Synthesis of11,12-dimethylene-13-oxa-tricyclo[7.3.1.0^(1,7)]tridecane

1.30 mL of ether was added to2-(2-hydroxy-4-trimethylsilanylmethyl-hexa-4,5-dienyl)-cycloheptanone(95 mg, 0.32 mmol) under nitrogen atmosphere. While stirring at −78° C.,TMSOTf (58.4 μL, 0.32 mmol) was added. While stirring the reactionmixture, the reaction temperature was slowly increased to roomtemperature for 3 hours. The reaction mixture was stirred at roomtemperature for 30 minutes. After the reaction was completed, H₂O wasadded. After stirring for about 5 minutes, the reaction mixture wasdiluted with EtOAc and washed with water and saturated brine. Theorganic layer was separated from the reaction mixture and dried withanhydrous MgSO₄. The solvent was removed under reduced pressure and theremaining material was purified with column chromatography(EtOAc/n-hexane=1/6) to obtain 59 mg of the product (90%).

¹H NMR (600 MHz, CDCl₃) δ 5.18 (s, 1H), 5.10 (s, 1H), 4.7 6(s, 1H), 4.49(s, 1H), 2.69 (s, 1H, J=14.2 Hz), 2.14 (d, 1H, J=14.4 Hz), 1.90 (m, 5H),1.54 (m, 4H), 1.50 (m, 2H), 1.18 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ153.59, 144.90, 111.98, 105.15, 86.91, 75.53, 47.81, 42.55, 40.41,34.63, 34.00, 31.98, 29.72, 25.08 ppm.

Comparative Example Diels-Alder Reaction using

9,10-dimethylene-12-oxa-tricyclo[6.3.1.0^(2,7)]dodeca-2,3,5-triene

The following is an example of synthesizing another multicyclic compoundby Diels-Alder from the compound represented by Chemical Formula 1.

2.0 mL of benzene was added to9,10-dimethylene-12-oxa-tricyclo[6.3.1.0^(2,7)]dodeca-2,3,5-triene (37mg, 0.2 mmol) under nitrogen atmosphere. After adding dimethylacetylenedicarboxylate (85.62 mg, 0.6 mmol), the reaction mixture was stirredwith reflux at 85° C. for 5 hours. After the reaction was completed, H₂Owas added. After stirring for about 5 minutes, the reaction mixture wasdiluted with ethyl acetate and washed with water and saturated brine.The organic layer was separated from the reaction mixture and dried withanhydrous MgSO₄. The solvent was removed under reduced pressure and theremaining material was purified with column chromatography(EtOAc/n-hexane=1/6) to obtain 39 mg of the product (60%).

¹H NMR (300 MHz, CDCl₃) δ 7.17 (m, 4H), 5.42 (d, 1H, J=5.97 Hz), 4.92(s, 1H), 3.77 (s, 1H), 3.73 (s, 1H), 2.84 (m, 6H); ¹³C NMR (75 MHz,CDCl₃) δ 168.7, 147.7, 142.9, 133.6, 131.2, 130.4, 128.2, 127.4, 127.3,121.4, 119.7, 117.8, 79.9, 78.8, 52.7, 32.9, 32.4, 28.9 ppm.

As described above, the present invention offers the followingadvantages:

1) Dimethylene cyclic compounds having a variety of structures can besynthesized using trimethylsilanylmethyl-alenol derivative as a startingmaterial.

2) The synthesis reaction is simple.

3) The synthesis yield is high.

4) The diexomethylene cyclic compound is useful as an intermediate ofsynthesizing multicyclic compounds having a 7-membered ring, which arevery important in the field of precise chemistry, by Diels-Alderreactions.

While the present invention has been described in detail with referenceto the preferred embodiments, those skilled in the art will appreciatethat various modifications and substitutions can be made thereto withoutdeparting from the spirit and scope of the present invention as setforth in the appended claims.

1-8. (Cancelled).
 9. A 7-membered carbocyclic compound withdiexomethylene groups having the formula (I):

wherein R¹ is a C₁ to C₆ alkyl group, and R² and R³ is each a hydrogenatom, or R¹, R² and R³ are connected with neighboring substituents toform a 5 to 10-membered aliphatic or aromatic ring.
 10. The compound ofclaim 9, wherein R¹ is C₁ to C₃ alkyl, and each of R² and R³ is ahydrogen atom.
 11. The compound of claim 9, wherein R¹ and R² areconnected with each other to form a 5 to 10-membered aliphatic oraromatic ring, and R³ is a hydrogen atom.
 12. The compound of claim 9,wherein R² and R³ are connected with each other to form a 5 to10-membered aliphatic or aromatic ring, and R¹ is a hydrogen atom. 13.The compound of claim 10, wherein R¹ is methyl.
 14. The compound ofclaim 9, wherein R¹ is phenyl, and each of R² and R³ are hydrogen. 15.The compound of claim 12, wherein R² and R³ are connected with eachother to form a phenyl group.
 16. The compound of claim 11, wherein R¹and R² are connected with each other to form a cyclopentyl group. 17.The compound of claim 11, wherein R¹ and R² are connected with eachother to form a cyclohexyl group.
 18. The compound of claim 11, hereinR¹ and R² are connected with each other to form a cycloheptyl group. 19.The compound of claim 9, which is1-methyl-2,3-dimethylene-8-oxa-bicyclo[3.2.1]octane.
 20. The compound ofclaim 9, which is 2,3-dimethylene-1-phenyl-8-oxa-bicyclo[3.2.1]octane.21. The compound of claim 9, which is9,10-dimethylene-12-oxa-tricyclo[6.3.1.0^(2,7)]dodeca-2,3,5-triene. 22.The compound of claim 9, which is9,10-dimethylene-11-oxa-tricyclo[5.3.1.0^(1,5)]undecane.
 23. Thecompound of claim 9, which is10,11-dimethylene-12-oxa-tricyclo[6.3.1.0^(1,6)]dodecane.
 24. Thecompound of claim 9, which is11,12-dimethylene-13-oxa-tricyclo[7.3.1.0^(1,7)]tridecane.
 25. A methodof synthesizing a 7-membered carbocyclic compound with diexomethylenegroups, and having the formula (I), which comprises reacting atrimethylsilanylmethyl-allenol compound by intramolecular Prinscyclization in the presence of a Lewis acid:

wherein R¹ is a C₁ to C₆ alkyl group, and R² and R³ is each a hydrogenatom, or R¹, R² and R³ are connected with neighboring substituents toform a 5 to 10-membered aliphatic or aromatic ring.
 26. The method ofclaim 25, wherein the reaction is conducted in a solvent selected fromthe group consisting of diethyl ether, tetrahydrofuran, dichloromethaneand chloroform.
 27. The method of claim 25, wherein said Lewis acid istrimethylsilyl trifluoromethanesulfonate (TMSOTf) and is used in anamount of 1.0 to 1.5 equivalent of said trimethylsilanylmethyl-allenolcompound.
 28. The method of claim 25, wherein the reaction is effectedat a temperature in the range from −90° C. to 25° C.
 29. The method ofclaim 25, wherein the reaction is effected at −78° C.
 30. The method ofclaim 26, wherein the solvent is diethyl ether.
 31. The method of claim25, wherein the reaction is effected for 3 to 5 hours.
 32. The method ofclaim 25, wherein the 7-membered carbocyclic compound is1-methyl-2,3-dimethylene-8-oxa-bicyclo[3.2.1]octane.
 33. The method ofclaim 25, herein the 7-membered carbocyclic compound is2,3-dimethylene-1-phenyl-8-oxa-bicyclo[3.2.1]octane.
 34. The method ofclaim 25, wherein the 7-membered carbocyclic compound is9,10-dimethylene-12-oxa-tricyclo[6.3.1.0^(2,7)]dodeca-2,3,5-triene. 35.The method of claim 25, wherein the 7-membered carbocyclic compound is9,10-dimethylene-11-oxa-tricyclo[5.3.1.0^(1,5)]undecane.
 36. The methodof claim 25, wherein the 7-membered carbocyclic compound is10,11-dimethylene-12-oxa-tricyclo[6.3.1.0^(1,6)]dodecane.
 37. The methodof claim 25, wherein the 7-membered carbocyclic compound is11,12-dimethylene-13-oxa-tricyclo[7.3.1.0^(1,7)]tridecane.
 38. A methodof preparing a 7-membered carbocyclic compound with diexomethylenegroups, which comprises subjecting a trimethylsilanyl-allenol compoundto an intramolecular Prins cyclization in the presence of a Lewis acid,to produce said 7-membered carbocyclic compound in a yield of at least77%.
 39. The method of claim 38, wherein the yield is at least 90%. 40.A method of preparing a Diels-Alder reaction product, which comprisessubjecting the 7-membered carbocyclic compound of claim 9, to aDiels-Alder reaction.